Identification of fluorescent ruthenium complexes containing imidazole derivatives as a new class of apoptosis inducers by living cell real-time imaging

Abstract

Chemical properties of metal complexes render them exciting scaffolds for the design of synthetic compounds with novel bioactivities. This report describes the discovery of a new class of mitochondria-targeting apoptosis inducers by living cell real-time imaging. In this study, a series of fluorescent ruthenium complexes have been synthesized and evaluated for their in vitro anticancer activities. The results showed that RuIP1 possessed great selectivity between human cancer and normal cells and displayed application potential in cancer chemotherapy. Studies were also carried out to elucidate the molecular mechanisms through which they caused the cancer cell death. These results showed that treatments with RuIP1 induced a dose-dependent depletion of mitochondrial membrane potential in A375 cells. Western blot analysis showed that RuIP1 induced caspase-mediated apoptosis in A375 cells, which was accompanied by DNA fragmentation, nuclear condensation, poly(ADP-ribose) polymerase (PARP) cleavage and activation of caspase-3, -8, -9. These results suggest that RuIP1 induced cancer cell apoptosis through activation of intrinsic and extrinsic pathways. RuIP1 also triggered the loss of mitochondrial membrane potential (ΔΨ_m) by regulating the expression of Bcl-2 family members. Taken together, RuIP1 was a novel apoptosis-inducer that was able to trigger caspase-mediated apoptosis in cancer cells.